Annual Rates of Events (AR) per 100 patient-year /
Severity

Base Case

Lower / Upper
(± 25%)

Probability Distribution

References

AR Systemic Embolism (SE)
ASA
Rivaroxaban
SE severity (%) (all therapies):
Non-fatal
Fatal

0.17
0.03

91
9

0.13 – 0.21
0.006 – 0.04

68 – 114
7 - 11

Beta
Beta

25
28

27
27

AR Ischemic Stroke (IS)
ASA
Rivaroxaban
IS severity with ASA (%):
Transient (< 24h)
Minor (mRS 0 - 2)
Major (mRS 3 – 5)
Fatal (mRS 6)
IS severity with rivaroxaban (%):
Transient (< 24h)
Minor (mRS 0 - 2)
Major (mRS 3 – 5)
Fatal (mRS 6)

1.38
0.87

36
38
15
11

50
13
11
26

1.04 – 1.73
0.65 – 1.09

27 – 45
29 – 48
11 – 19
8 – 14

38 – 63
10 – 16
8 – 14
20 - 33

Beta
Beta

Beta
Beta
Beta
Beta

25
28

27
27
27
27

29
29
29
29

AR Intracranial Haemorrhage (ICH)
ASA
Rivaroxaban
ICH severity with ASA (%):
Minor (mRS 0 – 2)
Major (mRS 3 – 5)
Fatal (mRS 6)
ICH severity with rivaroxaban (%):
Minor (mRS 0 – 2)
Major (mRS 3 – 5)
Fatal (mRS 6)

0.08
0.33

17
37
46

24
27
49

0.06 – 0.1
0.25 – 0.41

13 – 21
28 – 46
35 – 58

18 – 32
20 – 34
37 – 61

Beta
Beta

Beta
Beta
Beta

25
28

27
27
27

29
29
29

AR Major Bleed (extracranial)
ASA
Rivaroxaban
Major Bleed severity (%) (all therapies):
Non-fatal
Fatal

0.26
2.34

98
2

0.20 – 0.33
1.76 – 2.90

74 – 122
1 - 3

Beta
Beta

25
28

27
27

AR Clinically Relevant Minor Bleed
ASA
Rivaroxaban

2.63
7.67

1.97 – 3.29
5.75 – 9.59

Beta
Beta

25
28

AR Myocardial infarction (MI)
ASA
Rivaroxaban
MI severity (%) (all therapies):
Non-fatal
Fatal

0.42
0.59

89
11

0.32 – 0.53
0.44 – 0.74

67 – 111
8 - 14

Beta
Beta

25
28

27
27

AR Cognitive decline (CD)
ASA
Rivaroxaban

Hazard ratio (CHADS2-VASC = 0 - 1)

CD severity (%) (all therapies):
Mild (CDR 0.5 - 1)
Moderate (CDR 2)
Severe (CDR 3)
Fatal

1.78
1.14

0.85

77
16
1
6

1.34 – 2.23
0.86 – 1.43

0.64 – 1.06

58 – 96
12 – 20
0.75 – 1.25
4 - 8

Beta
Beta

Beta

Beta
Beta
Beta
Beta

30
30

30

31
31
31
31

AR Death (non-vascular)
ASA
Rivaroxaban

1.0
0.22

0.75 – 1.25
0.17 – 0.28

Beta
Beta

26,55
28

Table 1: Input Parameters

All rivaroxaban event rates from the ROCKET-AF trial reduced by 35%
ASA = acetyl salicylic acid; CDR = clinical dementia rating scale; mRS = modified Rankin scale adapted by the Oxfordshire Community Stroke Project to assess patient functional deficits at hospital discharge.

Health State	Utility/Decrement Base Case	Lower Value (2.50%)	Upper Value (97.50%)	Probability Distribution	References
NVAF	0.81000	0.67819	0.91373	Beta	32,33
SE	- 0.1199	-0.10224	-0.13880	Beta	32,33
IS Minor Severe	- 0.1385 - 0.2958	- 0.1184 - 0.2372	- 0.1600 - 0.3554	Beta Beta	32,33 25,27
ICH Minor Major	- 0.1385 - 0.2958	- 0.1182 - 0.2372	- 0.1602 - 0.3554	Beta Beta	32,33 25,27
MI	- 0.1247	-0.10645	-0.14356	Beta	32,33
Major bleed (extracranial)	- 0.1814	-0.15476	-0.20899	Beta	32,33
CRNM bleed	- 0.0582	-0.02429	-0.09211	Beta	25,27,34
Cognitive decline Mild Moderate Severe	- 0.13 - 0.27 - 0.44	(Base Case -25%) - 0.01 - 0.11 - 0.31	(Base Case + 25%) - 0.29 - 0.51 - 0.56	Beta Beta Beta	35,36 35,36 35,36

Table 2: Multivariate analysis of the factors related to poor glycemic control

ASA = acetyl salicylic acid; CRNM Bleed = clinically relevant non major bleed; ICH = intracranial hemorrhages; IS = ischemic stroke; MI = myocardial infarction; NVAF = non valvular atrial fibrillation; SE = systemic embolism.

Cost of Event	Adjusted Cost*	Lower/Upper Values	Probability Distribution	Source
SE	$9,610.42	7,208 – 12,013	Gamma	37
IS
Fatal	$19,200	14,400 – 24,000	Gamma	38
Minor	$19,200	14,400 – 24,000	Gamma	38
Major	$65,055.46	48,791 – 81,319	Gamma	38
Transient	$4,914.85	3,686 – 6,144	Gamma	38
ICH
Minor	$18,944.38	4,736 – 23,680	Gamma	38
Major	$37,865	28,399 – 47,331	Gamma	Assumption
Fatal	$18,944.38	4,736 – 23,680	Gamma	38
Major bleed (extracranial)	$5,024.68	3,769 – 6,281	Gamma	38
CRNM bleed	$118.98	89 - 149	Gamma	38
MI fatal	$8,409.94	6,308 – 10,513	Gamma	38
MI non-fatal	$13,019.33	9,764 – 16,274	Gamma	38
Minor CD	$797 (3 months)	598 - 996	Gamma	39
Moderate CD	$1015 (3 months)	761 - 1268	Gamma	39
Severe CD	$16066 (3 months)	12,050 – 20,083	Gamma	39

Long Term Costs (per annum)
MI	$3,743.34	2,807 – 4,679	Gamma	38
Major stroke	$21,809.09	16,357 – 27,261	Gamma	38
Minor stroke	$9,033.45	2,258 – 11,291	Gamma	38
ICH	$9,033.45	2,258 – 11,291	Gamma	38
SE	$2,256.94	1,693 – 2,821	Gamma	37

Drug Treatment (per 3 months)**
ASA – 100 mg (generic)	$12.97	11 – 15	Fixed	41
Rivaroxaban 15 mg	$284	241 - 327	Fixed	41

Table 3: Cost Inputs

* Cost estimated using 2020 inflation rate
ASA = acetyl salicylic acid; CD = cognitive decline; CRNM Bleed = clinically relevant non major bleed; ICH = intracranial hemorrhages; IS = ischemic stroke; MI = myocardial infarction; SE = systemic embolism.
** Cost of drugs is based on the “Liste des Médicaments - Régie d’Assurance Maladie du Québec”, November 2020 with $8.50 prescription fee and 8% mark-up.

Parameter	Rivaroxaban ICER (With Parameter Low Value)	Rivaroxaban ICER (With Parameter High Value)
Base Case ± 15%
Cost of Rivaroxaban	$29,440	$30,413
Cost of ASA	$29,914	$29,886
Base Case ± 25%
Cost of major IS	$29,891	$29,909
Cost of minor IS	$30,092	$29,708
Cost of fatal IS	$29,919	$29,882
Cost of major ICH	$29,889	$29,912
Cost of minor ICH	$29,894	$29,907
Cost of fatal ICH	$29,888	$29,913
Cost of SE	$29,935	$29,865
Cost of MI	$29,844	$29,957
Cost of fatal MI	$29,896	$29,904
Cost of major bleed	$26,964	$32,840
Cost of minor bleed	$29,899	$29,902
Cost of minor CD	$29,929	$29,872
Cost of moderate CD	$29,917	$29,883
Cost of severe CD	$30,010	$29,790
Base Case ± (CI)
Minor IS utility decrement	$29,885	$29,915
Major IS utility decrement	$29,891	$29,909
Minor ICH utility decrement	$29,901	$29,900
Major ICH utility decrement	$29,901	$29,899
SE utility decrement	$29,898	$29,908
MI utility decrement	$29,906	$29,894
Major bleed utility decrement	$31,162	$28,737
CRNMB utility decrement	$29,900	$29,900
Base Case ± 25%
Minor CD utility decrement	$29,866	$29,935
Moderate CD utility decrement	$29,866	$29,936
Severe CD utility decrement	$29,877	$29,922
Base Case ± 25%
Rate of IS with Rivaroxaban	$28,850	$31,143
Rate of IS with ASA	$32,970	$27,315
Rate of ICH with Rivaroxaban	$29,074	$30,578
Rate of ICH with ASA	$30,270	$29,900
Rate of SE with rivaroxaban	$29,842	$29,998
Rate of SE with ASA	$30,365	$29,630
Rate of MI with rivaroxaban	$28,388	$31,783
Rate of MI with ASA	$30,927	$28,952
Rate of MB with rivaroxaban	$23,578	$35,644
Rate of MB with ASA	$30,426	$29,025
Rate of CRNMB with rivaroxaban	$30,070	$29,719
Rate of CRNMB with ASA	$29,682	$29,953
Rate of CD with rivaroxaban	$29,448	$30,366
Rate of CD with ASA	$33,770	$26,984
Rate of non-vascular death with rivaroxaban	$29,736	$30,758
Rate of non-vascular death with ASA	$31,989	$28,198
Base case ± (low, high values)
Discount rate (low = 0, High = 3%)	$30,163	$29,665
Cycle length (1 month, 6 months)	$47,984	$15,211

Time horizon 10 years 20 years 40 years	$29,298 $28,245 $29,168

Table A1: Results of Deterministic Sensitivity Analyses

ICER = Incremental cost-effectiveness ratio;
CI = Confidence interval; IS = Ischemic stroke; ICH = Intracranial hemorrhage; SE = Systemic embolism; MI = Myocardial infarction; MB = Other major bleed; CD= Cognitive decline; CRNMB = Clinically relevant non major bleed

Strategy	Cost¨	D Cost¨	QALYs	D QALY	Incremental cost per QALY (ICER) vs ASA
ASA 100 mg	$75,086		14.1			Undominated
Rivaroxaban 15 mg	$273,073	$197,987	20.7	6.6	$29,900**	undominated

Tables at a glance

Figures at a glance